Recall of preexisting cross-reactive B cell memory after Omicron BA.1 breakthrough infection
Chengzi I. Kaku, Alan Bergeron, Clas Ahlm, Johan Normark, Mrunal Sakharkar, Mattias N.E. Forsell, Laura M. Walker
Abstract
Understanding immune responses after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) breakthrough infection will facilitate the development of next-generation vaccines. Here, we profiled spike (S)-specific B cell responses after Omicron/BA.1 infection in messenger RNA-vaccinated donors. The acute antibody response was characterized by high levels of somatic hypermutation and a bias toward recognition of ancestral SARS-CoV-2 strains, suggesting the early activation of vaccine-induced memory B cells. BA.1 breakthrough infection induced a shift in B cell immunodominance hierarchy from the S2 subunit, which is highly conserved across SARS-CoV-2 variants of concern (VOCs), and toward the antigenically variable receptor binding domain (RBD). A large proportion of RBD-directed neutralizing antibodies isolated from BA.1 breakthrough infection donors displayed convergent sequence features and broadly recognized SARS-CoV-2 VOCs. Together, these findings provide insights into the role of preexisting immunity in shaping the B cell response to heterologous SARS-CoV-2 variant exposure.